Use of antibacterial agents has grown rapidly over the past few years and so has the resistance of bacterial strains to antibiotics that use these agents as detailed by Sharma Rashmi et al; Indian J Med Sci 2005 in their article: “Antibacterial resistance: Current problems and possible solutions”. New range of bacterial strains that are resistant to multiple drugs has also evolved.
Penicillin, which is the first known antibiotic, has exhibited an excellent efficacy toward Staphylococci. However, penicillin resistant bacteria that degrade penicillin, emerged with the period of time. Research and development of penicillinase resistant penicillins (PRP) such as methicillin and cephems antibiotics provided solutions in clinical aspects to many problems posed by the penicillin resistant bacteria.
However, in recent years, as a result of overuse and misuse of third-generation cephem antibiotics, which have weak antibacterial potency on staphylococci and which are resistant to these antibiotics have selectively proliferated. Such bacteria have come to spread in hospitals, leading to rise in number of cases of hospital acquired infections. In particular, methicillin-resistant Staphalococcus aureus bacteria, commonly known as MRSA, has emerged, against which all known beta-lactam agents are ineffective. MRSA is an example of multiple-drug-resistant bacteria that are broadly resistant to not only penicillin antibiotics but also cephem antibiotics and aminoglycoside antibiotics individually. Examples of currently used antibiotics against MRSA infections include formulations containing glycopeptides such as vancomycin (VCM) and the like. However, VCM is involved in resistance to bacteria such as MRSA as discussed in ‘Emergence of low level vancomycin resistance in MRSA’ by Assadullah S et al 2003.
In addition, combinations of multiple antibiotics have been conventionally investigated aiming at the enhancement of antibacterial potency in an article ‘Re-emerging Staphylococci Infections’ by Barry Kreiswirth. Therefore, there exists an urgent need to the development of novel antibacterial combination drugs which are effective on resistant bacteria and can act synergistically as is done in the invention.
There have been many attempts to combat broad-spectrum gram negative and gram positive bacteria. These include administration of multiple antibacterial agents such as vancomycin and ceftriaxone. Ceftriaxone is less active against gram positive cocci than first generation cephalosporin. However, it is markedly active against gram negative bacteria such as Enterobacteriaceae including beta lactamase producing strains and penicillin resistant strains such as Haemophilus influenzae, Neisseria gonorrhoeaea and N. meningitis. It is also active against Staphylococcus aureus including penicillinase producing strains but not against methicillin resistant Staphylococcus aureus. Whereas vancomycin acts against variety of gram positive bacteria including methicillin resistant Staphylococcus aureus and Staph. epidermidis. Vancomycin shows high level acquired transferable resistance against Enterococci which appears to be plasmid mediated.
The use of multiple antibacterial agents for prevention and treatment of a variety of infectious disease states are found to be synergistic in vitro Ribes S et al J Antimicrob Chemother 2005 in their article explained that an additive effect was observed when combinations of ceftriaxone plus vancomycin were studied at sub inhibitory concentrations.
The emergence of multidrug-resistant pneumococci and, more recently, of pneumococci tolerant to vancomycin are important public health concerns worldwide (Henriques Normark et al, Clin. Infect. Dis. 2001; Novak, R, Nature 1999; R. M. Atkinson et al 40th Intersci. Conf. Antimicrob. Agents Chemother., 2000; A. Marchese, et al 40th Intersci. Conf. Antimicrob. Agents Chemother., 2000).
Various earlier investigations show that combination of vancomycin and ceftriaxone is more active against bacteria than monotherapy alone against commonly encountered pathogens in bacterial meningitis. Violeta Rodriguez-Cerrato, Antimicrob Agents Chemother. 2003; the aims of their study were to assess the bacteriologic effectiveness of these agents against experimental meningitis caused by vancomycin tolerant pneumococci and to compare the results with those obtained by conventional therapy with vancomycin and ceftriaxone in combination.
‘Rifampicin+ceftriaxone versus vancomycin+ceftriaxone in the treatment of penicillin- and cephalosporin-resistant pneumococcal meningitis in an experimental rabbit model’ by Suntur B M et al in Int J Antimicrob Agents. 2005 found Ceftriaxone+rifampicin was as effective as ceftriaxone+vancomycin.
Kaplan S L (2002) found that ceftriaxone and vancomycin are useful in the treatment and management of pneumococcal meningitis. Kaplan mentions that the standard empiric therapy for suspected bacterial meningitis for infants and children older than 1 month of age is the combination of cefotaxime or ceftriaxone and vancomycin. Treatment is modified after antimicrobial susceptibilities are available.
Jaing, T H, et al, in their 2002 publication reported a treatment of meningitis caused by highly-penicillin-resistant Streptococcus mitis in a leukemic child. The paper reported the case of a patient that was successfully treated with a combination of vancomycin, ceftriaxone, and granulocyte-colony-stimulating factor.
Cottangnoud P et. al. (2002) found that in experimental rabbit meningitis, cefepime given at a dose of 100 mg/kg was associated with concentrations in the cerebrospinal fluid of between 5.3 and 10 mg/L and a bactericidal activity of −0.61+/−0.24 Delta log(10) cfu/mL×h, similar to the standard regimen of ceftriaxone combined with vancomycin (−0.58+/−0.14 Delta log(10) cfu/mL×h) in the treatment of meningitis due to a penicillin- and quinolone-resistant pneumococcal mutant strain (MIC 4 mg/L).
Banon et. al. (2001) worked on time-kill evaluation in Spain. In this study the bactericidal activity of four antimicrobial regimens against ten clinical isolates of S. pneumoniae (five with an intermediate resistance to penicillin and five highly resistant ones), was determined by means of kill kinetics studies using either penicillin, or ceftriaxone, in combination with vancomycin, or fosfomycin.
Desbiolles et. al (2001) worked on fractional maximal effect method for in vitro synergy between amoxicillin and ceftriaxone, and between vancomycin and ceftriaxone, against Enterococcus faecalis and penicillin-resistant Streptococcus pneumoniae. They reported an assessment of the use of a new in vitro testing method and graphical representation of the results to investigate the potential effectiveness of combinations of amoxicillin (AMZ) plus ceftriaxone (CRO), and of CRO plus vancomycin (VAN) against strains of Streptococcus pneumoniae (PRP strains) highly resistant to penicillin and cephalosporins. Consequently, either of the combinations was proposed for use for the treatment of PRP infections.
Huebner et. al. (2000) reported that ceftriaxone or cefotaxime should be used in combination with vancomycin for the treatment of meningitis until a cephalosporin-resistant pneumococcal cause is excluded.
Roos (1999) studied bacterial meningitis therapy using a combination of third generation cephalosporins and vancomycin. He has suggested that initial empiric therapy for community-acquired bacterial meningitis should be based on the possibility that penicillin-resistant pneumococci may be the etiologic organisms and, hence, should include a combination of third-generation cephalosporin (cefotaxime or ceftriaxone) and vancomycin.
Climo et. al., 1999 found that combinations of vancomycin and beta-lactams are synergistic against staphylococci with reduced susceptibilities to vancomycin. Evidence of synergism between combinations multiple antibacterial agents such as vancomycin and cephalosporins against 59 isolates of methicillin-resistant staphylococci (Staphylococcus aureus, Staphylococcus epidermidis, and Staphylococcus haemolyticus) was collected. They concluded that the combination of vancomycin and beta-lactams with antistaphylococcal activity is an effective regiment for the treatment of infections with clinical strains of staphylococci which demonstrate reduced susceptibility to glycopeptides.
In a study of antimicrobial resistance of invasive Streptococcus pneumoniae in Slovenia, 1993-1995, Cizman M et. al. (1997) found that all penicillin-resistant isolates (intermediate resistance) were susceptible to cefotaxime, ceftriaxone and vancomycin.